- Email: [email protected]
Therapy of secondary hyperparathyroidism with 19-nor-1alpha,25- dihydroxyvitamin D2
Therapy of Secondary Hyperparathyroidism With 19-Nor -1␣, 25-Dihydroxyvitamin D2 Kevin J. Martin, MB, BCh, FACP, Esther A. Gonza´lez, MD, Mary E. Gellens, MD, L. Lee Hamm, MD, Hanna Abboud, MD, and Jill Lindberg, MD ● Secondary hyperparathyroidism contributes to significant morbidity in patients with chronic renal failure. The treatment of this disorder with vitamin D compounds, such as calcitriol, although effective at suppressing parathyroid hormone (PTH) secretion, may promote the development of hypercalcemia and hyperphosphatemia, thus increasing the risk for metastatic calcification. A new vitamin D analogue, 19-nor-1␣,25-(OH)2D2 (paricalcitol; Zemplar, Abbott Laboratories, Inc, Chicago, IL) has recently been developed for the treatment of secondary hyperparathyroidism, and, in experimental animals, it was found to be less calcemic and phosphatemic than calcitriol. In double-blind clinical trials, paricalcitol effectively decreased the levels of PTH by 60%, yet the mean serum calcium values remained within the normal range. The few episodes of hypercalcemia that occurred in the paricalcitol-treated patients (8 of 400 determinations H11.0 mg/dL in 7 patients) were associated with marked decreases in PTH levels (87% ⴞ 2% less than baseline) and absolute values of PTH less than 100 pg/mL in four of the seven patients. PTH values less than 100 pg/mL, however, occurred in 15 patients, but were not invariably associated with frank hypercalcemia, although serum calcium levels increased to 10.63 ⴞ 0.3 mg/dL, slightly greater than the upper limits of normal. Additional studies to evaluate the conversion from calcitriol to paricalcitol therapy showed that a dose ratio of 1:4 (calcitriol:paricalcitol) could maintain control of high levels of PTH without significant alterations in serum calcium and phosphorus levels. These studies indicate that effective control of hyperparathyroidism can be achieved with paricalcitol therapy with minimal perturbation of serum calcium and phosphorus levels, and may have a therapeutic advantage over current treatment strategies. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Hyperparathyroidism; vitamin D; calcitrol analogues.
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ECONDARY hyperparathyroidism continues to be a significant complication of chronic renal failure.1,2 Because of the importance of phosphorous retention and low levels of calcitriol in its pathogenesis, current therapy involves the use of dietary phosphorous restriction, phosphate-binding antacids to limit the absorption of ingested phosphorus, and the administration of vitamin D metabolites, such as calcitriol.3-5 Because of the marked effect of calcitriol in increasing intestinal calcium absorption, the concomitant use of calcitriol with large doses of calcium-containing phosphate-binding antacids increases the risk for hypercalcemia. Similarly, because calcitriol also increases intestinal phosphorus absorption, hyperphosphatemia may be aggravated during therapy with calcitriol.6 The need to improve our therapies for secondary hyperparathyroidism has led to a search for analogues of vitamin D that might have less effect on the absorption of calcium and phosphorous, and yet retain the effects of vitamin D on the suppression of parathyroid hormone (PTH) synthesis. Several new vitamin D analogues have been evaluated in this regard. One such analogue, 19-nor-1␣,25-dihydroxyvitamin D2 (paricalcitol), has been shown in experimental ani-
mals to suppress PTH levels as effectively as calcitriol, but with lesser effects on serum calcium and phosphorous levels.7 On the basis of these results in experimental animals, paricalcitol has been evaluated in patients with secondary hyperparathyroidism and end-stage renal disease undergoing maintenance hemodialysis.8 PATIENTS AND METHODS
Studies of Safety and Effıcacy Seventy-eight patients with end-stage renal disease (ESRD) were studied in three identical double-blind, placebocontrolled, randomized, multicenter trials to evaluate the safety and efficacy of paricalcitol. The results of such studies are described in detail elsewhere.8 All patients had ESRD and received hemodialysis three times a week. The study protocol is shown in diagrammatic form in Fig 1. In brief, if From the Division of Nephrology, Saint Louis University, St Louis, MO; Section of Nephrology, Tulane University; Department of Nephrology, Ochsner Clinic, New Orleans, LA; and the Division of Nephrology, University of Texas at San Antonio, TX. Supported in part by Abbott Laboratories, Abbott Park, IL. Address reprint requests to Kevin J. Martin, MB, BCh, FACP, Saint Louis University Health Sciences Center, Division of Nephrology (9-FDT), 3635 Vista Ave, St Louis, MO 63110. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 6386/98/3204-0207$3.00/0
American Journal of Kidney Diseases, Vol 32, No 4, Suppl 2 (October), 1998: pp S61-S66
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albumin level less than 4 g/dL had their total serum calcium level normalized to an albumin level of 4.0 g/dL.
Statistical Analysis Data are presented as mean ⫾ standard error of the mean (SEM). Paricalcitol-treated patients were compared with placebo-treated patients using a one-way analysis of variance for continuous variables and Fisher’s exact test for categorical variables. Student’s t-test was used for comparisons as indicated. For the conversion studies, analysis of variance followed by Bonferroni t-test was used. Fig 1. Diagram of the protocol for the study of the safety and efficacy of paricalcitol. For complete description, see text. Reproduced with permission.8 Abbreviations: Ca, calcium; Pi, phosphorus.
the patients were receiving calcitriol, it was withdrawn, and a 2-week washout period elapsed before entering the baseline period. If the patients were not receiving calcitriol, the baseline observation period was begun. During this time, the levels of intact PTH, serum calcium, and phosphorous were measured weekly for 2 weeks, after which patients were randomized to receive either placebo or paricalcitol intravenously after each hemodialysis session, and the studies were continued for 12 weeks. The study protocol called for incrementing the dose of paricalcitol, provided that PTH levels had not decreased by greater than 30%, serum calcium had not increased to greater than 11.5 mg/dL, and the calcium-phosphorous product was less than 75. If serum calcium values exceeded 11.5 mg/dL or an elevated calciumphosphate product or intact PTH levels less than 100 pg/mL were encountered, the dose of paricalcitol was reduced. Otherwise, the administered dose was maintained for the duration of the study. Intact PTH, serum calcium, and phosphorous levels were measured on a weekly basis.
RESULTS
The levels of PTH in the paricalcitol-treated group are shown in Fig 2. The mean value for intact PTH values decreased from 785 ⫾ 66 to 370 ⫾ 73 pg/mL during the 12 weeks of the study, representing approximately a 50% decrease in PTH level. The maximum dose of paricalcitol that was administered was 0.12 ⫾ 0.1 µg/kg of body weight. No change in PTH levels was observed in those patients receiving the placebo (data not shown). Figure 2 also shows that this dramatic decrease in the levels of PTH occurred without any major change in the levels of serum calcium compared with the baseline values. Thus, normalized serum calcium values were 9.24 ⫾ 0.12
Studies of Conversion From Calcitriol to Paricalcitol Additional studies were performed to evaluate the feasibility of converting patients in whom PTH levels were controlled using calcitriol to paricalcitol therapy. A group of 29 patients who had been receiving calcitriol intravenously postdialysis for at least 3 months and who had received a stable dose of calcitriol for at least 1 month were entered into the study and followed up with measurements of intact PTH, serum calcium, and phosphorus levels at weekly intervals for 4 consecutive weeks while continuing to receive calcitriol after each dialysis treatment. Then, therapy was abruptly switched to paricalcitol at a dose ratio of 1:4. Thus, if patients were receiving 1 µg of calcitriol, they would then receive 4 µg of paricalcitol. The levels of intact PTH, serum calcium, and phosphorus were measured weekly for an additional 4 weeks.
Analytic Methods Serum chemistries and PTH determination by immunoradiometric assay (IRMA) were performed in a central laboratory by Covance, Indianapolis, IN. Because for every 1-g/dL decrease in serum albumin level there is a decrease in protein-bound calcium level of 0.8 mg/dL, patients with an
Fig 2. The levels of intact PTH in the patients receiving paricalcitol are depicted by the solid bars. The shaded area above the bars represents the normal range for serum calcium levels, and contains the values for normalized serum calcium levels throughout the study. Data are shown as mean ⴞ SEM.
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mg/dL at baseline and 9.56 ⫾ 0.15 mg/dL at the end of the study, a small but statistically significant increase (P ⬍ 0.02), but remained within the normal range. The mean values for serum phosphorous did not change significantly during therapy with paricalcitol, and were 5.86 ⫾ 0.24 mg/dL at baseline and 6.35 ⫾ 0.32 mg/dL after 12 weeks of paricalcitol (P ⫽ not significant [NS]). The decrease in PTH values appeared to have a significant effect on the skeleton in that the paricalcitol-treated group had a significant decrease in serum alkaline phosphatase levels from 148 ⫾ 23 to 101 ⫾ 14 U/L (P ⬍ 0.001), whereas no change occurred in those receiving placebo (120 ⫾ 9 U/L before and 130 ⫾ 11 U/L after receiving placebo for 12 weeks). During the course of the study, there were only a few transient episodes of elevations in serum calcium level, with only eight determinations in seven patients that exceeded 11 mg/dL and three determinations that exceeded 11.5 mg/dL of the more than 400 determinations of serum calcium in each group during the studies.8 In the seven patients in whom the calcium level reached or exceeded 11.0 mg/dL, the values for PTH and calcium are shown in Fig 3. Four of the seven
Fig 3. The values for intact PTH and the corresponding serum calcium for the seven patients who became hypercalcemic during therapy with paricalcitol.
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Fig 4. The values for serum calcium, phosphorus, and intact PTH in patients receiving calcitriol (open bars), and after 4 weeks after the substitution of calcitriol with paricalcitol (solid bars). Data are shown as mean ⴞ SEM.
patients had reductions in PTH levels to less than 100 pg/mL; in two of the seven patients; PTH levels decreased to less than 165 pg/mL, and the remaining patient had a dramatic decrease in PTH level from a very elevated value of greater than 2,000 pg/mL to 239 pg/mL. To analyze whether the elevated serum calcium levels (calcium ⱖ 11.0 mg/dL) only occurred when PTH levels decreased to very low levels, the database was reviewed to select those patients in whom the PTH values decreased to less than 100 pg/ mL. Fifteen patients had PTH values decrease to less than 100 pg/mL, including four of the seven previously described patients who became hypercalcemic, with serum calcium levels exceeding 11.0 mg/dL. In these patients, the mean PTH level was 572 ⫾ 49 pg/mL and the serum calcium level was 9.19 ⫾ 0.17 mg/dL at entry. When PTH levels decreased to less than 100 pg/mL (mean values, 75 ⫾ 5 pg/mL), serum calcium levels had increased to 10.63 ⫾ 0.3 mg/dL, slightly greater than the upper limits of normal. Thus, in general, it appears that a PTH level of less than 100 pg/mL is associated with an increase in serum calcium level to or greater than the upper limits of normal. Further studies were then performed to evaluate the ability to change from therapy with calcitriol to paricalcitol. Figure 4 shows the results of studies performed in a group of 29 patients who were stable on intravenous calcitriol therapy and were monitored weekly with determinations of PTH, calcium, and phosphorous levels for 4 weeks. Subsequently, paricalcitol therapy was substituted for calcitriol during the following 4 weeks while continuing to monitor the levels of serum calcium, phosphorus, and PTH on a weekly
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basis. As shown in Fig 3, none of the parameters measured changed significantly during therapy, with paricalcitol compared with calcitriol. Normalized serum calcium values were 9.07 ⫾ 0.19 mg/dL at the end of the monitoring period on calcitriol and 9.3 ⫾ 0.16 mg/dL after 4 weeks on therapy with paricalcitol (P ⫽ NS). Phosphorous values were 5.4 ⫾ 0.29 mg/dL on calcitriol therapy and 5.25 ⫾ 0.24 mg/dL on paricalcitol (P ⫽ NS). The levels of intact PTH, which were controlled to 281 ⫾ 17.9 pg/mL on calcitriol, were 292 ⫾ 23 pg/mL after 4 weeks on paricalcitol therapy (P ⫽ NS). In these studies, a dose ratio of 1:4 was used; that is, for every microgram of calcitriol that was administered in the initial period, four micrograms of paricalcitol was administered after the switch over. Thus, therapy could be changed from calcitriol to paricalcitol using this dose ratio while effectively maintaining the control of hyperparathyroidism without an untoward effect on calcium and phosphorous levels. DISCUSSION
The use of vitamin D metabolites, such as calcitriol, together with the use of phosphatebinding antacids has been effective in the control of hyperparathyroidism.3,4,9-11 However, hypercalcemia is encountered not infrequently because of the marked effect of calcitriol to increase intestinal calcium absorption. Similarly, it has often been noted that hyperphosphatemia may be aggravated by calcitriol therapy. This is consistent with the observation that calcitriol also increases the intestinal absorption of phosphorous.6 In an effort to dissociate the effects of vitamin D on calcium and phosphorous metabolism while maintaining the effects of the sterol on other tissues, such as the parathyroid,12-14 analogues of vitamin D have been sought that have less calcemic activity than calcitriol but retain some of the other properties of vitamin D metabolites on cellular processes, such as the regulation of gene transcription.15 One such analogue, 19-nor 1-␣25-dihydroxyvitamin D2 (paricalcitol), was found in vitro to be as effective as calcitriol in decreasing PTH secretion from bovine parathyroid cells.7 In vivo, in experimental animals with renal insufficiency, this compound had less calcemic and phosphatemic effects than calcitriol and yet was effective in suppressing PTH levels.7
Because of these properties found in experimental animals, which were believed to be desirable for therapy in humans, this vitamin D analogue was then evaluated in clinical trials in double-blind, placebo-controlled studies. The results, which are described in detail elsewhere,8 showed that this vitamin D analogue could safely and effectively decrease the levels of PTH in patients with secondary hyperparathyroidism. Thus, paricalcitol could achieve a greater than 50% decrease in the levels of PTH when administered with each hemodialysis, and yet this decrease in PTH occurred with minimal effect on serum calcium and phosphorous levels. There were some episodes of elevation of serum calcium levels to 11.0 mg/dL or greater, however, and although few in number (eight occurrences in seven patients during the 12 weeks of study), they only occurred when PTH levels decreased to very low values. In other patients, however, if PTH levels decreased to values of less than 100 pg/mL, frank hypercalcemia was not observed, although serum calcium values increased to or slightly greater than the upper limits of normal. It is not possible to determine from these studies whether it was the hypercalcemia that resulted in the marked decrease in PTH level or, conversely, whether the marked decrease in the levels of PTH predisposed to the onset of hypercalcemia as a result of impaired skeletal buffering of alterations in serum calcium caused by low bone turnover. In general, it would not appear to be desirable to allow PTH values to decrease to such low levels because of the risk for contributing to a state of abnormally low bone turnover and adynamic bone histology. The desired range for PTH values in patients with ESRD receiving vitamin D metabolite therapy is not precisely known, but PTH values in the range of 150 to 300 pg/mL may be required for normal rates of bone turnover.16,17 These clinical studies suggest that paricalcitol can safety and effectively decrease the levels of PTH and have less influence on serum calcium and phosphorous levels than previous experience has shown with calcitriol. Accordingly, paricalcitol may have a wider therapeutic window between efficacy and toxicity than calcitriol and thus may offer an advantage for the therapy of hyperparathyroidism. Whereas bone histology was not evaluated in these studies, the decrease
PARICALCITOL FOR HYPERPARATHYROIDISM
in serum alkaline phosphatase level in the paricalcitol-treated patients is at least suggestive that the decrease in PTH levels may have biological significance at the level of bone. Further studies will be required to evaluate this in detail. Additional studies were performed to evaluate the conversion of therapy with calcitriol to paricalcitol. In a group of patients in whom the PTH levels were controlled to values between 250 and 300 pg/mL on a stable dose of calcitriol, switching their therapy to paricalcitol using a dose ratio of 1:4 (calcitriol:paricalcitol) appeared to be satisfactory in that PTH levels remained under control and the serum values of calcium and phosphorus did not change significantly. Thus, it would appear that one could use this dose ratio, ie, for every 1 µg of calcitriol, substitute 4 µg of paricalcitol, to initiate or convert therapy to paricalcitol using previous experience with calcitriol as a guide. The explanation for the apparent selectivity of the actions of this vitamin D analogue is not clear at the present time. Studies in experimental animals have shown that the administration of paricalcitol can result in the suppression of PTH levels, and, unlike calcitriol, it is not associated with increases in intestinal vitamin D receptor content, which potentially could limit the absorption of calcium and phosphorus in response to the analogue.18 Furthermore, paricalcitol appears to be less potent than calcitriol in mobilizing calcium from the skeleton.19 In addition, the selectivity of paricalcitol compared with calcitriol cannot be explained by differences in pharmacokinetics, which appear to explain, at least in part, the less calcemic effect of other vitamin D analogues, such as 22-oxacalcitriol.20 Clearly, additional studies are required to try to define the details of the mechanism of action of this analogue. In summary, the clinical studies have shown that the vitamin D analogue, paricalcitol, is effective in suppressing elevated levels of PTH in patients with ESRD undergoing hemodialysis with minimal effect on the levels of serum calcium and phosphorus. These data support the concept that analogues of vitamin D that have less calcemic and phosphatemic actions than calcitriol may be beneficial for the therapy of secondary hyperparathyroidism in patients with
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advanced renal failure, and may be coming of age in clinical medicine. ACKNOWLEDGMENT The authors thank Linda McCloud, Patricia Gibson, and Casey Warner for assistance in the performance of these studies.
REFERENCES 1. Malluche H, Faugere MC: Renal bone disease 1990: An unmet challenge for the nephrologist. Kidney Int 38:193211, 1990 2. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in end-stage renal failure—An evolving disorder. Kidney Int 43:436-442, 1993 3. Delmez JA, Slatopolsky E: Hyperphosphatemia: Its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 19:303-317, 1992 4. Gonza´lez EA, Martin KJ: Renal osteodystrophy: Pathogenesis and management. Nephrol Dial Transplant 10:1321, 1995 (suppl 3) 5. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 74:21362143, 1984 6. Brickman AS, Hartenbower DL, Norman AW, Coburn JW: Actions of 1 alpha-hydroxyvitamin D3 and 1,25dihydroxyvitamin D3 on mineral metabolism in man. I. Effects on net absorption of phosphorus. Am J Clin Nutr 30:1064-1069, 1977 7. Slatopolsky E, Finch J, Ritter C, Denda M, Morrissey J, Brown A, DeLuca H: A new analog of calcitriol, 19-nor1,25-(OH)2D2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis 26:852-860, 1995 8. Martin KJ, Gonza´lez EA, Gellens M, Hamm LL, Abboud H, Lindberg J: 19-Nor-1-␣-25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact PTH in patients on hemodialysis. J Am Soc Nephrol 10:1427-1432, 1998 9. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald PN, Brown AJ: Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97: 2534-2540, 1996 10. Slatopolsky E, Berkoben M, Kelber J, Brown A, Delmez J: Effects of calcitriol and non-calcemic vitamin D analogs on secondary hyperparathyroidism. Kidney Int Suppl 38:S43-S49, 1992 11. Coburn J, Salusky I: Hyperparathyroidism in renal failure: Clinical features, diagnosis and management, in Bilezikian J, Levine M, Marcus R (eds): The Parathyroids: Basic and Clinical Concepts. New York, NY, Raven, 1994, pp 721-745 12. Okazaki T, Igarashi T, Kronenberg HM: 58-flanking region of the parathyroid hormone gene mediates negative regulation by 1,25-(OH)2 vitamin D3. J Biol Chem 263:22032208, 1988
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13. Russell J, Lettieri D, Sherwood LM: Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 119:2864-2866, 1986 14. Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM: Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 78:1296-1301, 1986 15. Bikle DD: Clinical counterpoint: Vitamin D: New actions, new analogs, new therapeutic potential. Endocr Rev 13:765-784, 1992 16. Wang M, Hercz G, Sherrard DJ, Maloney NA, Segre GV, Pei Y: Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 26:836844, 1995 17. Quarles LD, Lobaugh B, Murphy G: Intact parathy-
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roid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia. J Clin Endocrinol Metab75:145-150, 1992 18. Takahashi F, Finch JL, Denda M, Dusso AS, Brown AJ, Slatopolsky E: A new analog of 1,25-(OH)2D3, 19-nor1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis 30:105-112, 1997 19. Finch JL, Brown AJ, Slatopolsky E: Differential effects of 19-nor-1,25-(OH)2D2 on calcium and phosphate resorption in bone. J Am Soc Nephrol 8:573A, 1997 (abstr) 20. Brown AJ, Finch J, Takahashi F, Ritter CS, Slatopolsky E: Distinct mechanisms for the selective actions of two vitamin D analogues, 19-nor-1,25 (OH)2D2 and 22-oxa-1,25 (OH)2D3. J Am Soc Nephrol 8:571A, 1997 (abstr)
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ECONDARY hyperparathyroidism continues to be a significant complication of chronic renal failure.1,2 Because of the importance of phosphorous retention and low levels of calcitriol in its pathogenesis, current therapy involves the use of dietary phosphorous restriction, phosphate-binding antacids to limit the absorption of ingested phosphorus, and the administration of vitamin D metabolites, such as calcitriol.3-5 Because of the marked effect of calcitriol in increasing intestinal calcium absorption, the concomitant use of calcitriol with large doses of calcium-containing phosphate-binding antacids increases the risk for hypercalcemia. Similarly, because calcitriol also increases intestinal phosphorus absorption, hyperphosphatemia may be aggravated during therapy with calcitriol.6 The need to improve our therapies for secondary hyperparathyroidism has led to a search for analogues of vitamin D that might have less effect on the absorption of calcium and phosphorous, and yet retain the effects of vitamin D on the suppression of parathyroid hormone (PTH) synthesis. Several new vitamin D analogues have been evaluated in this regard. One such analogue, 19-nor-1␣,25-dihydroxyvitamin D2 (paricalcitol), has been shown in experimental ani-
mals to suppress PTH levels as effectively as calcitriol, but with lesser effects on serum calcium and phosphorous levels.7 On the basis of these results in experimental animals, paricalcitol has been evaluated in patients with secondary hyperparathyroidism and end-stage renal disease undergoing maintenance hemodialysis.8 PATIENTS AND METHODS
Studies of Safety and Effıcacy Seventy-eight patients with end-stage renal disease (ESRD) were studied in three identical double-blind, placebocontrolled, randomized, multicenter trials to evaluate the safety and efficacy of paricalcitol. The results of such studies are described in detail elsewhere.8 All patients had ESRD and received hemodialysis three times a week. The study protocol is shown in diagrammatic form in Fig 1. In brief, if From the Division of Nephrology, Saint Louis University, St Louis, MO; Section of Nephrology, Tulane University; Department of Nephrology, Ochsner Clinic, New Orleans, LA; and the Division of Nephrology, University of Texas at San Antonio, TX. Supported in part by Abbott Laboratories, Abbott Park, IL. Address reprint requests to Kevin J. Martin, MB, BCh, FACP, Saint Louis University Health Sciences Center, Division of Nephrology (9-FDT), 3635 Vista Ave, St Louis, MO 63110. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 6386/98/3204-0207$3.00/0
American Journal of Kidney Diseases, Vol 32, No 4, Suppl 2 (October), 1998: pp S61-S66
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albumin level less than 4 g/dL had their total serum calcium level normalized to an albumin level of 4.0 g/dL.
Statistical Analysis Data are presented as mean ⫾ standard error of the mean (SEM). Paricalcitol-treated patients were compared with placebo-treated patients using a one-way analysis of variance for continuous variables and Fisher’s exact test for categorical variables. Student’s t-test was used for comparisons as indicated. For the conversion studies, analysis of variance followed by Bonferroni t-test was used. Fig 1. Diagram of the protocol for the study of the safety and efficacy of paricalcitol. For complete description, see text. Reproduced with permission.8 Abbreviations: Ca, calcium; Pi, phosphorus.
the patients were receiving calcitriol, it was withdrawn, and a 2-week washout period elapsed before entering the baseline period. If the patients were not receiving calcitriol, the baseline observation period was begun. During this time, the levels of intact PTH, serum calcium, and phosphorous were measured weekly for 2 weeks, after which patients were randomized to receive either placebo or paricalcitol intravenously after each hemodialysis session, and the studies were continued for 12 weeks. The study protocol called for incrementing the dose of paricalcitol, provided that PTH levels had not decreased by greater than 30%, serum calcium had not increased to greater than 11.5 mg/dL, and the calcium-phosphorous product was less than 75. If serum calcium values exceeded 11.5 mg/dL or an elevated calciumphosphate product or intact PTH levels less than 100 pg/mL were encountered, the dose of paricalcitol was reduced. Otherwise, the administered dose was maintained for the duration of the study. Intact PTH, serum calcium, and phosphorous levels were measured on a weekly basis.
RESULTS
The levels of PTH in the paricalcitol-treated group are shown in Fig 2. The mean value for intact PTH values decreased from 785 ⫾ 66 to 370 ⫾ 73 pg/mL during the 12 weeks of the study, representing approximately a 50% decrease in PTH level. The maximum dose of paricalcitol that was administered was 0.12 ⫾ 0.1 µg/kg of body weight. No change in PTH levels was observed in those patients receiving the placebo (data not shown). Figure 2 also shows that this dramatic decrease in the levels of PTH occurred without any major change in the levels of serum calcium compared with the baseline values. Thus, normalized serum calcium values were 9.24 ⫾ 0.12
Studies of Conversion From Calcitriol to Paricalcitol Additional studies were performed to evaluate the feasibility of converting patients in whom PTH levels were controlled using calcitriol to paricalcitol therapy. A group of 29 patients who had been receiving calcitriol intravenously postdialysis for at least 3 months and who had received a stable dose of calcitriol for at least 1 month were entered into the study and followed up with measurements of intact PTH, serum calcium, and phosphorus levels at weekly intervals for 4 consecutive weeks while continuing to receive calcitriol after each dialysis treatment. Then, therapy was abruptly switched to paricalcitol at a dose ratio of 1:4. Thus, if patients were receiving 1 µg of calcitriol, they would then receive 4 µg of paricalcitol. The levels of intact PTH, serum calcium, and phosphorus were measured weekly for an additional 4 weeks.
Analytic Methods Serum chemistries and PTH determination by immunoradiometric assay (IRMA) were performed in a central laboratory by Covance, Indianapolis, IN. Because for every 1-g/dL decrease in serum albumin level there is a decrease in protein-bound calcium level of 0.8 mg/dL, patients with an
Fig 2. The levels of intact PTH in the patients receiving paricalcitol are depicted by the solid bars. The shaded area above the bars represents the normal range for serum calcium levels, and contains the values for normalized serum calcium levels throughout the study. Data are shown as mean ⴞ SEM.
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mg/dL at baseline and 9.56 ⫾ 0.15 mg/dL at the end of the study, a small but statistically significant increase (P ⬍ 0.02), but remained within the normal range. The mean values for serum phosphorous did not change significantly during therapy with paricalcitol, and were 5.86 ⫾ 0.24 mg/dL at baseline and 6.35 ⫾ 0.32 mg/dL after 12 weeks of paricalcitol (P ⫽ not significant [NS]). The decrease in PTH values appeared to have a significant effect on the skeleton in that the paricalcitol-treated group had a significant decrease in serum alkaline phosphatase levels from 148 ⫾ 23 to 101 ⫾ 14 U/L (P ⬍ 0.001), whereas no change occurred in those receiving placebo (120 ⫾ 9 U/L before and 130 ⫾ 11 U/L after receiving placebo for 12 weeks). During the course of the study, there were only a few transient episodes of elevations in serum calcium level, with only eight determinations in seven patients that exceeded 11 mg/dL and three determinations that exceeded 11.5 mg/dL of the more than 400 determinations of serum calcium in each group during the studies.8 In the seven patients in whom the calcium level reached or exceeded 11.0 mg/dL, the values for PTH and calcium are shown in Fig 3. Four of the seven
Fig 3. The values for intact PTH and the corresponding serum calcium for the seven patients who became hypercalcemic during therapy with paricalcitol.
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Fig 4. The values for serum calcium, phosphorus, and intact PTH in patients receiving calcitriol (open bars), and after 4 weeks after the substitution of calcitriol with paricalcitol (solid bars). Data are shown as mean ⴞ SEM.
patients had reductions in PTH levels to less than 100 pg/mL; in two of the seven patients; PTH levels decreased to less than 165 pg/mL, and the remaining patient had a dramatic decrease in PTH level from a very elevated value of greater than 2,000 pg/mL to 239 pg/mL. To analyze whether the elevated serum calcium levels (calcium ⱖ 11.0 mg/dL) only occurred when PTH levels decreased to very low levels, the database was reviewed to select those patients in whom the PTH values decreased to less than 100 pg/ mL. Fifteen patients had PTH values decrease to less than 100 pg/mL, including four of the seven previously described patients who became hypercalcemic, with serum calcium levels exceeding 11.0 mg/dL. In these patients, the mean PTH level was 572 ⫾ 49 pg/mL and the serum calcium level was 9.19 ⫾ 0.17 mg/dL at entry. When PTH levels decreased to less than 100 pg/mL (mean values, 75 ⫾ 5 pg/mL), serum calcium levels had increased to 10.63 ⫾ 0.3 mg/dL, slightly greater than the upper limits of normal. Thus, in general, it appears that a PTH level of less than 100 pg/mL is associated with an increase in serum calcium level to or greater than the upper limits of normal. Further studies were then performed to evaluate the ability to change from therapy with calcitriol to paricalcitol. Figure 4 shows the results of studies performed in a group of 29 patients who were stable on intravenous calcitriol therapy and were monitored weekly with determinations of PTH, calcium, and phosphorous levels for 4 weeks. Subsequently, paricalcitol therapy was substituted for calcitriol during the following 4 weeks while continuing to monitor the levels of serum calcium, phosphorus, and PTH on a weekly
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basis. As shown in Fig 3, none of the parameters measured changed significantly during therapy, with paricalcitol compared with calcitriol. Normalized serum calcium values were 9.07 ⫾ 0.19 mg/dL at the end of the monitoring period on calcitriol and 9.3 ⫾ 0.16 mg/dL after 4 weeks on therapy with paricalcitol (P ⫽ NS). Phosphorous values were 5.4 ⫾ 0.29 mg/dL on calcitriol therapy and 5.25 ⫾ 0.24 mg/dL on paricalcitol (P ⫽ NS). The levels of intact PTH, which were controlled to 281 ⫾ 17.9 pg/mL on calcitriol, were 292 ⫾ 23 pg/mL after 4 weeks on paricalcitol therapy (P ⫽ NS). In these studies, a dose ratio of 1:4 was used; that is, for every microgram of calcitriol that was administered in the initial period, four micrograms of paricalcitol was administered after the switch over. Thus, therapy could be changed from calcitriol to paricalcitol using this dose ratio while effectively maintaining the control of hyperparathyroidism without an untoward effect on calcium and phosphorous levels. DISCUSSION
The use of vitamin D metabolites, such as calcitriol, together with the use of phosphatebinding antacids has been effective in the control of hyperparathyroidism.3,4,9-11 However, hypercalcemia is encountered not infrequently because of the marked effect of calcitriol to increase intestinal calcium absorption. Similarly, it has often been noted that hyperphosphatemia may be aggravated by calcitriol therapy. This is consistent with the observation that calcitriol also increases the intestinal absorption of phosphorous.6 In an effort to dissociate the effects of vitamin D on calcium and phosphorous metabolism while maintaining the effects of the sterol on other tissues, such as the parathyroid,12-14 analogues of vitamin D have been sought that have less calcemic activity than calcitriol but retain some of the other properties of vitamin D metabolites on cellular processes, such as the regulation of gene transcription.15 One such analogue, 19-nor 1-␣25-dihydroxyvitamin D2 (paricalcitol), was found in vitro to be as effective as calcitriol in decreasing PTH secretion from bovine parathyroid cells.7 In vivo, in experimental animals with renal insufficiency, this compound had less calcemic and phosphatemic effects than calcitriol and yet was effective in suppressing PTH levels.7
Because of these properties found in experimental animals, which were believed to be desirable for therapy in humans, this vitamin D analogue was then evaluated in clinical trials in double-blind, placebo-controlled studies. The results, which are described in detail elsewhere,8 showed that this vitamin D analogue could safely and effectively decrease the levels of PTH in patients with secondary hyperparathyroidism. Thus, paricalcitol could achieve a greater than 50% decrease in the levels of PTH when administered with each hemodialysis, and yet this decrease in PTH occurred with minimal effect on serum calcium and phosphorous levels. There were some episodes of elevation of serum calcium levels to 11.0 mg/dL or greater, however, and although few in number (eight occurrences in seven patients during the 12 weeks of study), they only occurred when PTH levels decreased to very low values. In other patients, however, if PTH levels decreased to values of less than 100 pg/mL, frank hypercalcemia was not observed, although serum calcium values increased to or slightly greater than the upper limits of normal. It is not possible to determine from these studies whether it was the hypercalcemia that resulted in the marked decrease in PTH level or, conversely, whether the marked decrease in the levels of PTH predisposed to the onset of hypercalcemia as a result of impaired skeletal buffering of alterations in serum calcium caused by low bone turnover. In general, it would not appear to be desirable to allow PTH values to decrease to such low levels because of the risk for contributing to a state of abnormally low bone turnover and adynamic bone histology. The desired range for PTH values in patients with ESRD receiving vitamin D metabolite therapy is not precisely known, but PTH values in the range of 150 to 300 pg/mL may be required for normal rates of bone turnover.16,17 These clinical studies suggest that paricalcitol can safety and effectively decrease the levels of PTH and have less influence on serum calcium and phosphorous levels than previous experience has shown with calcitriol. Accordingly, paricalcitol may have a wider therapeutic window between efficacy and toxicity than calcitriol and thus may offer an advantage for the therapy of hyperparathyroidism. Whereas bone histology was not evaluated in these studies, the decrease
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in serum alkaline phosphatase level in the paricalcitol-treated patients is at least suggestive that the decrease in PTH levels may have biological significance at the level of bone. Further studies will be required to evaluate this in detail. Additional studies were performed to evaluate the conversion of therapy with calcitriol to paricalcitol. In a group of patients in whom the PTH levels were controlled to values between 250 and 300 pg/mL on a stable dose of calcitriol, switching their therapy to paricalcitol using a dose ratio of 1:4 (calcitriol:paricalcitol) appeared to be satisfactory in that PTH levels remained under control and the serum values of calcium and phosphorus did not change significantly. Thus, it would appear that one could use this dose ratio, ie, for every 1 µg of calcitriol, substitute 4 µg of paricalcitol, to initiate or convert therapy to paricalcitol using previous experience with calcitriol as a guide. The explanation for the apparent selectivity of the actions of this vitamin D analogue is not clear at the present time. Studies in experimental animals have shown that the administration of paricalcitol can result in the suppression of PTH levels, and, unlike calcitriol, it is not associated with increases in intestinal vitamin D receptor content, which potentially could limit the absorption of calcium and phosphorus in response to the analogue.18 Furthermore, paricalcitol appears to be less potent than calcitriol in mobilizing calcium from the skeleton.19 In addition, the selectivity of paricalcitol compared with calcitriol cannot be explained by differences in pharmacokinetics, which appear to explain, at least in part, the less calcemic effect of other vitamin D analogues, such as 22-oxacalcitriol.20 Clearly, additional studies are required to try to define the details of the mechanism of action of this analogue. In summary, the clinical studies have shown that the vitamin D analogue, paricalcitol, is effective in suppressing elevated levels of PTH in patients with ESRD undergoing hemodialysis with minimal effect on the levels of serum calcium and phosphorus. These data support the concept that analogues of vitamin D that have less calcemic and phosphatemic actions than calcitriol may be beneficial for the therapy of secondary hyperparathyroidism in patients with
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advanced renal failure, and may be coming of age in clinical medicine. ACKNOWLEDGMENT The authors thank Linda McCloud, Patricia Gibson, and Casey Warner for assistance in the performance of these studies.
REFERENCES 1. Malluche H, Faugere MC: Renal bone disease 1990: An unmet challenge for the nephrologist. Kidney Int 38:193211, 1990 2. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in end-stage renal failure—An evolving disorder. Kidney Int 43:436-442, 1993 3. Delmez JA, Slatopolsky E: Hyperphosphatemia: Its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 19:303-317, 1992 4. Gonza´lez EA, Martin KJ: Renal osteodystrophy: Pathogenesis and management. Nephrol Dial Transplant 10:1321, 1995 (suppl 3) 5. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 74:21362143, 1984 6. Brickman AS, Hartenbower DL, Norman AW, Coburn JW: Actions of 1 alpha-hydroxyvitamin D3 and 1,25dihydroxyvitamin D3 on mineral metabolism in man. I. Effects on net absorption of phosphorus. Am J Clin Nutr 30:1064-1069, 1977 7. Slatopolsky E, Finch J, Ritter C, Denda M, Morrissey J, Brown A, DeLuca H: A new analog of calcitriol, 19-nor1,25-(OH)2D2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis 26:852-860, 1995 8. Martin KJ, Gonza´lez EA, Gellens M, Hamm LL, Abboud H, Lindberg J: 19-Nor-1-␣-25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact PTH in patients on hemodialysis. J Am Soc Nephrol 10:1427-1432, 1998 9. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald PN, Brown AJ: Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97: 2534-2540, 1996 10. Slatopolsky E, Berkoben M, Kelber J, Brown A, Delmez J: Effects of calcitriol and non-calcemic vitamin D analogs on secondary hyperparathyroidism. Kidney Int Suppl 38:S43-S49, 1992 11. Coburn J, Salusky I: Hyperparathyroidism in renal failure: Clinical features, diagnosis and management, in Bilezikian J, Levine M, Marcus R (eds): The Parathyroids: Basic and Clinical Concepts. New York, NY, Raven, 1994, pp 721-745 12. Okazaki T, Igarashi T, Kronenberg HM: 58-flanking region of the parathyroid hormone gene mediates negative regulation by 1,25-(OH)2 vitamin D3. J Biol Chem 263:22032208, 1988
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13. Russell J, Lettieri D, Sherwood LM: Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 119:2864-2866, 1986 14. Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM: Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 78:1296-1301, 1986 15. Bikle DD: Clinical counterpoint: Vitamin D: New actions, new analogs, new therapeutic potential. Endocr Rev 13:765-784, 1992 16. Wang M, Hercz G, Sherrard DJ, Maloney NA, Segre GV, Pei Y: Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 26:836844, 1995 17. Quarles LD, Lobaugh B, Murphy G: Intact parathy-
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roid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia. J Clin Endocrinol Metab75:145-150, 1992 18. Takahashi F, Finch JL, Denda M, Dusso AS, Brown AJ, Slatopolsky E: A new analog of 1,25-(OH)2D3, 19-nor1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis 30:105-112, 1997 19. Finch JL, Brown AJ, Slatopolsky E: Differential effects of 19-nor-1,25-(OH)2D2 on calcium and phosphate resorption in bone. J Am Soc Nephrol 8:573A, 1997 (abstr) 20. Brown AJ, Finch J, Takahashi F, Ritter CS, Slatopolsky E: Distinct mechanisms for the selective actions of two vitamin D analogues, 19-nor-1,25 (OH)2D2 and 22-oxa-1,25 (OH)2D3. J Am Soc Nephrol 8:571A, 1997 (abstr)